Proc.฀Intl.฀Soc.฀Mag.฀Reson.฀Med฀9฀(2001) 1307 ) Direct evidence of functional activation of Double Cortex detected by fMRI Michela Tosetti 1 , Domenico Montanaro 2 , Paolo Bonanni 3 , Marco Giannelli 3 , Alberto Spalice 4 , Raffaello Canapicchi 3 , Renzo Guerrini 5 1 Stella Maris Scientific Institute, MR Department, Calambrone, Pisa, Italy; 2 Neuroradiology Department, S. Chiara Hospital, Pisa, Italy; 3 Stella Maris Scientific Institute, Pisa, Italy; 4 Paediatric Department, University La Sapienza, Rome, Italy; 5 Academic Neuroscience Centre King's College Hospital, London, UK; Introduction Subcortical band (or laminar) heterotopia is a neuronal migration disorder characterized by circumferential bands of heterotopic gray matter located beneath the cortical ribbon and separated from it by a thin band of white matter. Mutations of the doublecortin gene on the X chromosome account for most cases. Because of its anatomic appearance the malformation was originally named double cortex, without any clear information on the functional properties and connectivity of the abnormally located neurons in the `second´ cortex. In order to study the functional response of the heterotopic cortex we performed functional MRI (fMRI) in 4 patients affected by double cortex. Methods 4 left handed female patients presenting a grossly abnormal bilateral extensive cerebral gray matter heterotopias (double cortex) were studied. In patient n. 1 (M.A.) there was a very large heterotopic band undistinguishable in some points from the cortex of the forebrain. Patients n. 2 (B.B.) had cortical sulcation and heterotopic band similar to patient n.1, but less severe. Patient n. 3 (P.A.) had less severe sulcal abnormality than patient n. 1 and n. 2; the heterotopic band was extended to all lobes, well delineated from the cortex and thicker on the left. In patient n.4 (M.A.) the heterotopic band was very thin, in particular on the left, extended to all lobes and well distinguishable from the cortex of the forebrain. Patients n. 1, 2, 3 had doublecortin gene mutations. BOLD responses were generated during fMRI studies performing motor and sensory tasks of the hands, motor tasks for lips and tongue and visual stimulus. Images were acquired with a 1.5 T General Electric Signa Horizon System (GE, Milwaukee, USA), equipped with Echo-speed gradient coil and amplifier hardware, using a standard quadrature head-coil. Activation images were acquired using echoplanar imaging (EPI) gradient-recalled echo sequence (TR/TE/flip angle = 3 s/50ms/90°, FOV = 280x210 mm, matrix = 128 x 96, Acquisition time: 3.13 min). Time-course series of 64 images for each volume, acquired every 3 s, were collected usually in 6 epochs alternating between control and active conditions, each 30 seconds in duration. In some sessions only 5 stimulus epochs were used. The first epoch always lasted 13 sec more to allow the signal to stabilise. This initial period was eliminated from any successive analysis. The original sampling volume matrix was resample to 128x128 pixels over 8-10 slices, with final voxel size of 2.19 x 2.19 x 5 mm. For mapping the different functions, a GUI based fMRI analysis software package (STIMULATE, University of Minnesota) was used [1]. BOLD maps for signal intensity changes were generated by temporal correlation of the T2*-weighted EPI images acquired with the task and baseline alternation sequences [2]. The correlation coefficient threshold used to create the functional maps was set at 0.2 for the visual task and to 0.35 for the other task with the additional requirement of a cluster size of 6 voxels. With these values it is possible to evaluate the effective probability, after considering the correction for multiple comparison to a value less than 0.01 for visual maps and to 0.001 for the others. To validate the activation localization we also analysed the same data using SPM-99 (Department of Cognitive Neurology, London) [3]. Results The visual stimulus, sensory tasks and tasks performed for opercular regions activated the primary and secondary cortical areas similar to control subjects´ variations. In all patients during motor tasks areas of activations were located in contralateral pre- and post-central region and in mesial frontal cortex. While the peri-central cortical areas of the hemisphere ipsilateral to movement was activated in all patients during the right motor performance, an analogous, contralateral, pattern of activation was seen only in one patient (Pat. 4) during the left hand task. In the lateral premotor cortex a response was revealed only in patients n°2 and n°3 during left hand task. The extension and the correct localization of the motor activations during the right hand task was similar to control subjects only in patient n°4. In two patients (1 and 2) the functional map showed, in the contralateral pre and post central regions, a pixel cluster spread along the dysplasic cortex underneath the rolandic sulcus. In the deepest part the pixel cluster involved the heterotopic cortex. In patient n°3, besides the normal cortical activations, during the right hand task there was also an isolated pixel cluster located in the double cortex beneath the primary motor cortex. All these three patients harboured a doublecortin mutation. Discussion These findings, which are in line with those reported in other PET and fMRI studies [4], could result from either a functional reorganization secondary to the malformation or a heterotopic representation of function subserved by a preserved columnar neuronal assembly, observed in neuropathological studies [5]. Moreover the feasibility of the fMRI study permits the mapping of the most important functions that could be very important for surgical planning to resolve the epilepsy often affecting these patients. References 1. Strupp JP. NeuroImage 1996; 3(3):S607. 2. Bandettini PA et al. Magn Reson Med 1993; 30, 161. 3. Friston KJ et al. Human Brain Map 1994; 1, 53. 4. Pinard et al. Neurology 2000; 54: 1531-1533. 5. Harding B. in “Dysplasias of cerebral cortex and epilepsy” Lipincott–Raven, 1996 ,81-88.